Human immunodeficiency virus (HIV-1)is the major cause of acquired immunodeficiency syndrome (AIDS) in humans. The HIV-1 envelope glycoproteins, gp120 and gp41, are contained in trimeric complexes on the virion surface. The gp120 envelope glycoprotein mediates virus attachment to target cell receptors, CD4 and the chemokine receptors, CCR5 or CXCR4. Receptor binding triggers conformational changes in the HIV-1 envelope glycoproteins leading to the fusion of the viral and target cell membranes, a process mediated by the gp41 transmembrane envelope glycoprotein. The HIV-1 envelope glycoproteins and receptors represent potential targets for pharmacologic intervention. The envelope glycoproteins are the sole target for virus-neutralizing antibodies and are likely to be an important component in an effective vaccine against HIV-1 infection. Both therapeutic and prophylactic approaches would benefit from information on the structure of the HIV-1 envelope glycoproteins and the receptors. The overall goal of this proposal is to achieve an atomic level understanding of the structural biology associated with the HIV-1 envelope glycoproteins, receptors and neutralizing antibodies. In Specific Aim 1, the structure of the monomeric HIV-1 gp120 glycoprotein in several different contexts will be determined. In Specific Aim 2, an attempt will be made to determine structures of HIV-1 envelope glycoprotein trimers. In Specific Aim 3, the structure of the CCR5 and CXCR4 chemokine receptors will be investigated.